Most current strategies for pharmacologic treatment of cancers are based on developing drugs or biologicals, primarily antibodies and anti-sense RNAs that specifically inhibit the activity of an enzyme in a signaling pathway or a gene encoding an enzyme upon which the cancer cell is dependent for growth and survival (Shoshan and Linder 2008). Dependence of a particular type of cancer on excessive activity of a specific signaling pathway has been termed “oncogene addiction” (Lim et al 2008). Interference with the function or abundance of an addicting oncogene may inhibit growth and, in some cases, result in the death of cancer cells that are dependent upon the pathway. Inhibition of a single oncogene, however, is usually insufficient for complete inhibition of a cancer and inhibition is overcome by mutation leading to drug resistance. Older approaches to cancer treatment have involved primarily the use of non-specific agents alone and in combinations of drugs with non-overlapping toxicities to normal tissues that damage DNA or interfere with cell metabolic pathways including modulation of microtubule stability.
A variety of mechanisms maintain the integrity of the genome of normal cells in the face of stress. DNA-damage response mechanisms, however, may also protect cancer cells from killing by chemotherapy and radiation, allowing cancers to recur despite aggressive treatment. Cell responses to DNA-damage are mediated in part by polo-like kinase 1 (Plk-1) (Strebhardt and Ullrich, 2006), Akt-1 (protein kinase B) (Brazil et al, 2004) and p53 (Vogelstein et al 2000; Vazquez et al 2008), pathways, which lead to cell cycle arrest, senescence, or apoptosis. Because many cancers over-express Plk-1 (Lei and Erikson, 2008; Olmos et al, 2008; Liu et al, 2006) and Akt-1 (Garcia-Echeverria and Sellers, 2008; Hirose et al 2005) or have acquired p53 (Vazquez et al, 2008) genetic defects, inhibition of Plk-1 (Strebhardt and Ullrich, 2006; Olmos et al, 2008; Liu et al, 2006) and Akt-1 (Garcia-Echeverria and Sellers, 2008; Hirose et al, 2005) and the restoration of p53 function (Vazquez et al, 2008) are being widely investigated as cancer treatments.
Translationally controlled tumor protein (TCTP) is one of the most highly conserved and most abundant proteins in eukaryotic cells (Bommer and Thiele, 2004). TCTP is associated with many cellular functions and is essential for fetal development (Bommer and Thiele, 2004; Chen et al, 2007B). TCTP is also essential to cancer cell growth but is not critical to the survival of normal adult (untransformed) cells (Chen et al, 2007). Disclosed herein is that targeting of TCTP with a pharmacologic intervention may be an effective means for disrupting cancer cell division and therefore for treating cancers in general.